Esters of p-carbonylphenoxy-isobutyric acids

ABSTRACT

This invention is concerned with esters of p-carbonylphenoxy-isobutyric acids of the general formulae: &lt;IMAGE&gt;  (I) and  &lt;IMAGE&gt; (Ia)  WHEREIN R is a phenyl group substituted by one or two halogen atoms; R&#39; is H, CH3, C6H5, SCH3, OCH3, or, SO2CH3; R&#39;&#39; is CH3 or C2H5; Y is C1-C4 alkoxy, phenoxy, phenoxy substituted by one or two halogen atoms, or, OCH2O-CO-C(CH3)3; Z is C1-C4 alkyl, phenyl or R; NR1R2 is N(CH3)2N(C2H5)2, morpholino, piperidino, azepino, pyrrolidino.

This application is a cip application of my previous U.S. Pat.application Ser. No. 326 188 of Jan. 24, 1973 now U.S. Pat. No.3,907,792 which was itself a cip application of my U.S. Pat. applicationSer. No. 8071 of Feb. 2, 1970 now U.S. Pat. 3,914,286.

This invention is concerned with esters of p-carbonylphenoxy-isobutyricacids.

This application is concerned with esters of the general formulae##STR2## WHEREIN R is a phenyl group substituted by one or two halogenatoms;

R' is H, CH₃, C₆ H₅, OCH₃, or, SO₂ CH₃ ;

R" is CH₃ or C₂ H₅

Y is C₁ - C₄ alkoxy, phenoxy, phenoxy substituted by one or two halogenatoms, or OCH₂ O--CO--C(CH₃)₃ ;

Z is C₁ -C₄ alkyl, phenyl, or, R₁

Nr₁ r₂ is N(CH₃)₂ N(C₂ H₅)₂, morpholino, piperidino, pyrrolidino, or,azepino.

This application is also concerned with acid addition salts obtainedfrom formula Ia compounds with inorganic and organic acids.

All the compounds of formula I and Ia have useful therapeuticproperties. All of them are lipids and cholesterol reducing agents,moreover they act as normolipidemiant and hypocho lesterolemiant agents.The acids (Y = OH): from which esters I and Ia derived, induce gastriculcers when administered by oral route, while their ester derivatives Iand Ia do not develop gastric ulcers.

Some acids of the isobutyric type have been previously disclosed orsuggested. AINSWORTH et al, J. Med. Chem., (1967), 10, 158-161 describedtwo acids, namely the p-hexanoyl- and p-octanoylphenoxyisobutyric acids.NAKANISHI (US patent No. 3 494957) suggested thep-acetylphenoxy-isobutyric acid. CRAGOE (US Pat. No. 3 704 314)suggested two acids, namely the p-butyrylphenoxy isobutyric acid and2,3-dichloro -4-(2-methylenebutyryl-phenoxy-isobutyric acid, and anester, namely the ethyl p-formylphenoxy-isobutyrate. On one hand theseknown acids present the disadvantage of inducing gastric ulcers, and onthe other hand ethyl p-formylphenoxy-isobutyrate is less active thanClofibrate taken as a reference product. By halogen atoms I meanfluorine, chlorine, bromine and iodine atoms, the preferred halogen atombeing chlorine. Thus, in the definition of R are included within thescope of this invention the 4-chlorophenyl, 3-chlorophenyl,3,4-dichlorophenyl and 2,6-dichlorophenyl groups. The preferred R groupis 4-chlorophenyl. The preferred R' and R" are respectively R' = H andR" = CH₃.

The esters of formula I are more active than their homologue compoundsin which R is alkyl or cycloalkyl such as cyclohexyl. Moreover when theesters are p-carbonylphenoxy-isobutyric acid aminoethyl esters (i.e.compounds of the formula Ia), it is noticed that the presence of theOCH₂ CH₂ NR₁ R₂ group enhances the hypocholesterolemiant andhypolipidemiant activities of the p-alkylcarbonyl compounds.

The preferred compound, that is to say the most useful therapeutically,is the isopropyl p-(4-chlorobenzoyl)-phenoxy-isobutyrate of formula I,which is coded as No. 178. Then comes the fumarate of β-azepino-ethylp-(4-chlorobenzoyl)-phenoxy-isobutyrate of formula Ia, which is coded asNo. 229.

The isobutyric acids (Y=OH) can be synthesized according to a methodknown per se. The methods I recommend are summed up by the followingreaction schemes A and B, scheme B being the preferred one since itgives higher yields than A. ##STR3##

The esters I and Ia are obtained from the acids by a known process. Forinstance the esters may be prepared by esterification from thecorresponding acids or by transesterification from another ester. Forobtaining esters Ia the transesterification method is preferred.

Preparation I

p-(4-Chlorobenzoyl)-phenoxy-isobutyric acid (Code No. 153) 1 mole of4-hydroxy-4'-chlorobenzophenone is dissolved in anhydrous acetone andthen 5 moles of powdered sodium hydroxide is added. The correspondingsodium phenate precipitates. Refluxing is effected, and then, 1.5 moleof CHCl₃ diluted with anhydrous acetone is added and the resultingmixture is refluxed for 10 hours. After cooling, water is added, theacetone is evaporated, the aqueous phase is washed with ether andacidified and the organic phase is redissolved in ether and extractedinto a solution of bicarbonate. The bicarbonate solution is thenacidified to obtain the desired acid, having a melting point of 185° C,with a yield of 75%.

Preparation II

Isopropyl (p-4-chlorobenzoyl)-phenoxy-isobutyrate ##STR4## 1 mole of theacid obtained in preparation I is converted into its acid chloride usingthionyl chloride (2.5 moles). 1 mole of the acid chloride is thencondensed with 1.05 mole of isopropyl alcohol in the presence of 0.98mole of pyridine in an inert solvent such as benzene.

Since traces of SO₂ (which has a bad smell) may be obtained from thethionyl chloride; it is preferable to avoid this disadvantage bycarrying out the esterification directly.

In table I, I have given examples of p-carbonylphenoxy-isobutyric acidswhich are used as intermediate compounds for the preparation of theesters according to this invention. They have been obtained according toreaction scheme A or B.

Tables II and III are respectively concerned with esters of formula Iand esters of formula Ia. I have given in table IV reference orcomparison products. Moreover, p-alkylcarbonyl-phenoxy-isobutyric acidesters of table IV may be used for preparing the corresponding esters Iaby transesterification.

                  TABLE I                                                         ______________________________________                                         ##STR5##                                                                     ______________________________________                                                                               Melting or                             Ex-   Code                             Boiling                                ample No.     R           R'      R"   point                                  ______________________________________                                        Ex 1   82    CH.sub.3 CH.sub.2                                                                          H       CH.sub.3                                                                           F=96° C                         Ex 2(a)      C.sub.6 H.sub.5                                                                            H       CH.sub.3                                    Ex 3(b)      CH.sub.3 (CH.sub.2).sub.4                                                                  H       CH.sub.3                                    Ex 4(b)      CH.sub.3 CH.sub.2).sub.6                                                                   H       CH.sub.3                                    Ex 5(c)      CH.sub.3     H       CH.sub.3                                    Ex 6(a)                                                                       (d)          CH.sub.3 (CH.sub.2).sub.2                                                                  H       CH.sub.3                                                                           F=88° C                         Ex 7  153    4-ClC.sub.6 H.sub.4                                                                        H       CH.sub.3                                                                           F=185° C                        Ex 8  198    CH.sub.3 (CH.sub.2).sub.3                                                                  H       CH.sub.3                                                                           F=62° C                         Ex 9  243    CH.sub.3     3-CH.sub.3                                                                            CH.sub.3                                                                           F=98° C                         Ex 10 --     CH.sub.3     2-C.sub.6 H.sub.5                                                                     CH.sub.3                                                                           F=106° C                        Ex 11 305    4-ClC.sub. 6 H.sub.4                                                                       H       C.sub.2 H.sub.5                                                                    F=140° C                        Ex 12 406    3-ClC.sub.6 H.sub.4                                                                        H       CH.sub.3                                                                           F=121° C                        Ex 13 404    3,4-Cl.sub.2C.sub.6 H.sub.3                                                                H       CH.sub.3                                                                           F=155° C                        Ex 14 401    2,6-Cl.sub.2C.sub.6 H.sub.3                                                                H       CH.sub.3                                                                           F=196° C                        Ex 15 391    cyclohexyl   H       CH.sub.3                                                                           F=146° C                        Ex 16 --     CH.sub.3     3-SO.sub.2 CH.sub.3                                                                   CH.sub.3                                                                           --                                     ______________________________________                                         Notes-                                                                        (a) disclosed in my previous U.S. Pat. Application Ser. No. 8071              (b) disclosed by AINSWORTH                                                    (c) suggested by NAKANISHI                                                    (d) suggested by CRAGOE                                                  

                                      TABLE II                                    __________________________________________________________________________     ##STR6##                                                                     __________________________________________________________________________                                    Melting or                                         Code                       Boiling                                       Example                                                                            No.                                                                               R      R'   Y          point                                         __________________________________________________________________________    Ex 17                                                                              162                                                                              4-ClC.sub.6 H.sub.4                                                                   H    OCH.sub.5  F=89° C                                Ex 18                                                                              163                                                                              4-ClC.sub.6 H.sub.4                                                                   H    OC.sub.2 H.sub.5                                                                         F=79° C                                Ex 19                                                                              178                                                                              4-ClC.sub.6 H.sub.4                                                                   H    OCH(CH.sub.3).sub.2                                                                      F=78° C                                Ex 20                                                                              217                                                                              4-ClC.sub.6 H.sub.4                                                                   H    p-OC.sub.6 H.sub.4 Cl                                                                    F=135° C                               Ex 21                                                                              403                                                                              3-ClC.sub.6 H.sub.4                                                                   H    OCH(CH.sub.3).sub.2                                                                      F=79° C                                Ex 22                                                                              405                                                                              3,4-Cl.sub.2C.sub.6 H.sub.3                                                           H    OCH(CH.sub.3).sub.2                                                                      F=69° C                                Ex 23                                                                              402                                                                              2,6-Cl.sub.2C.sub.6 H.sub.3                                                           H    OCH(CH.sub.3).sub.2                                                                      F=115° C                               Ex 24                                                                              253                                                                              4-ClC.sub.6 H.sub.4                                                                   3-CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                      --                                            Ex 25                                                                              297                                                                              4-ClC.sub.6 H.sub.4                                                                   H    OCH.sub.2 OCOC(CH.sub.3).sub.3                                                           F=80° C                                __________________________________________________________________________

                  table iii                                                       ______________________________________                                         ##STR7##                                                                     ______________________________________                                                                               melting or                                 Code                               Boiling                                Ex  No.    Z          R'  OCH.sub.2 CH.sub.2 NR.sub.1 R.sub.2                                                        point                                  ______________________________________                                        Ex 26                                                                             208    C.sub.6 H.sub.5                                                                          H                                                                                  ##STR8##    F = 100° C                      Ex 27                                                                             209    C.sub.6 H.sub.5                                                                          H                                                                                  ##STR9##    F = 118° C                      Ex 28                                                                             210    CH.sub.3   H                                                                                  ##STR10##   F = 134° C                      Ex 29                                                                             211    C.sub.6 H.sub.5                                                                          H                                                                                  ##STR11##   F = 115°  C                     Ex  212    C.sub.6 H.sub.5                                                                          H   OCH.sub.2 CH.sub.2 NEt.sub.2                                                               F =  62° C                      30                        maleate                                             Ex 31                                                                             229    4-ClC.sub.6 H.sub.4                                                                      H                                                                                  ##STR12##   F = 120° C                      Ex  230    4-ClC.sub.6 H.sub.4                                                                      H   OCH.sub.2 CH.sub.2 NEt.sub.2                                                               F = 104° C                      32                        HCl                                                 Ex 33                                                                             231    4-ClC.sub.6 H.sub.4                                                                      H                                                                                  ##STR13##   F = 116° C                      Ex  232    CH.sub.3 (CH.sub.2).sub.3                                                                H   OCH.sub.2 CH.sub.2 NEt.sub.2                                                               F =  72° C                      34                        HCl                                                 Ex 35                                                                             233    CH.sub.3 (CH.sub.2).sub.3                                                                H                                                                                  ##STR14##   F = 118° C                      Ex 36                                                                             239    4-ClC.sub.6 H.sub.5                                                                      H                                                                                  ##STR15##   F = 145° C                      ______________________________________                                    

                                      table iv                                    __________________________________________________________________________    reference, comparison and/or other intermediate compounds                      ##STR16##                                                                                                   Melting or                                          Code                      Boiling                                        Example                                                                            No.                                                                              R      R'    Y         point                                          __________________________________________________________________________    Ex 37 (c)                                                                          180                                                                              C.sub.6 H.sub.5                                                                      H     OCH.sub.3 F = 58° C                               Ex 38 (a)                                                                          186                                                                              C.sub.6 H.sub.5                                                                      H     OC.sub.2 H.sub.5                                                                        F = 87° C                               Ex 39 (a)                                                                          190                                                                              C.sub.6 H.sub.5                                                                      H     OCH(CH.sub.3).sub.2                                                                     F = 84° C                               Ex 40                                                                              -- CH.sub.3                                                                             H     OC.sub.2 H.sub.5                                                                        E.sub.0.03 = 120° C                     Ex 41                                                                              -- CH.sub.3 CH.sub.2 CH.sub.2                                                           H     OC.sub.2 H.sub.5                                                                        E.sub.0.005 = 144° C                    Ex 42                                                                              140                                                                              CH.sub.3                                                                             H     OCH.sub.3 F = 62° C                               Ex 43                                                                              188                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H     OCH.sub.3 E.sub. 0.05 = 147 - 9° C                Ex 44                                                                              187                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H     OC.sub.2 H.sub.5                                                                        E.sub.0.05 = 157 - 8° C                 Ex 45                                                                              189                                                                              CH.sub.3 (CH.sub.2).sub.3                                                            H     OCH(CH.sub.3).sub.2                                                                     E.sub.0.05 = 156 - 7° C                 Ex 46                                                                              -- H      H     OC.sub.2 H.sub.5                                                                        --                                             Ex 47                                                                              390                                                                              cyclohexyl                                                                           H     OCH(CH.sub.3).sub.2                                                                     F = 148° C                              Ex 48                                                                              238                                                                              4-ClC.sub.6 H.sub.5                                                                  H                                                                                    ##STR17##                                                                              F = 144° C                                                   HCl                                                      Ex 49                                                                              240                                                                              CH.sub.3                                                                             3-CH.sub.3                                                                          OCH.sub.3 E.sub.0.05 = 132° C                     Ex 50                                                                              241                                                                              CH.sub.3                                                                             3-CH.sub.3                                                                          OC.sub.2 H.sub.5                                                                        E.sub.0.05 = 136° C                     Ex 51                                                                              242                                                                              CH.sub.3                                                                             3-CH.sub.3                                                                          OCH(CH.sub.3).sub.2                                                                     E.sub.0.05 = 139° C                     Ex 52                                                                              -- CH.sub.3                                                                             3-SCH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                     E.sub.1 = 198° C                        Ex 53                                                                              -- CH.sub.3                                                                             3-SO.sub.2 CH.sub.3                                                                 OCH(CH.sub.3).sub.2                                                                     F =  86° C                              Ex 54                                                                              -- CH.sub.3                                                                             2-C.sub.6 H.sub.5                                                                   OCH(CH.sub.3).sub.2                                                                     F = 95° C                               __________________________________________________________________________     Notes (a) and (c) see table I                                            

The hypolipemiant and hypocholesterolemiant properties were exhibited inthe rat. Each batch of rats (15 animals) is put on a fast at time t = 0.A blood sample is taken at time t + 15 hours, and then each productbeing tested is immediately administered orally. A new blood sample istaken at time t + 39 hours. The variation (diminution) in the totalamount of blood cholesterol and total amount of blood lipids is measuredbetween t + 15 hours and t + 39 hours, and this variation is expressedin % in Table V in which the results obtained with the productsaccording to this invention and reference products are shown.

The invention also relates to therapeutic compositions containing, incombination with a physiologically acceptable excipient, at least onecompound of formula I or Ia or one of their non-toxic acid-additionsalts.

                  TABLE V                                                         ______________________________________                                                              variation   variation                                   Example   dosage      cholesterol lipids                                      (Code No.)                                                                              mg/kg       %           %                                           ______________________________________                                        Ex 19 (178)                                                                             50          - 30         - 32                                       Ex 21 (403)                                                                             100         - 21         - 18                                       Ex 22 (405)                                                                             100         - 10         -  4                                       Ex 23 (402)                                                                             100         -  9         -  5                                       Ex 27 (209)                                                                             75          - 19         - 34                                       Ex 31 (229)                                                                             50          - 35         - 34                                       Ex 36 (239)                                                                             50          - 18         - 22                                       Ex 24 (253)                                                                             70          - 15         - 25                                       Ex 28 (210)                                                                             400         - 35         - 16                                       Ex 35 (233)                                                                             300         - 16         - 15                                       Ex 38 (186)                                                                             100         - 21         - 32                                       Ex 39 (190)                                                                             50          - 30         - 32                                       Ex 40     300         - 28         - 34                                       Ex 41     400         - 22         - 31                                       Ex 47 (390)                                                                             100         N.S.         -  3                                       ______________________________________                                    

What is claimed is:
 1. A novel ester of p-carbonylphenoxy-isobutyricacid having the formula ##STR18## wherein R is a phenyl groupsubstituted by one or two halogen atoms;R' is H, CH₃, C₆ H₅, SCH₃, OCH₃,or, SO₂ CH₃ ; R" is CH₃ or C₂ H₅ ; and Y is C₁₋ C₄ alkoxy, phenoxy,phenoxy substituted by one or two halogen atoms, or, OCH₂ O-CO-C (CH₃)₃.2. A novel ester according to claim 1 having the formula ##STR19##wherein R is 4-ClC₆ H₄, 3-ClC₆ H₄, 3,4-(Cl)₂ - C₆ H₃ and 2,6-(Cl)₂ - C₆H₃, and, Y is OCH₃, OC₂ H₅, OCH(CH₃)₂.
 3. An ester ofp-carbonylphenoxy-isobutyric acid according to claim 1 wherein R is4-chlorophenyl.
 4. An ester of p-carbonylphenoxy-isobutyric acidaccording to claim 1 wherein R is 3,4-dichlorophenyl.
 5. Isopropylp-(4-chlorobenzoyl)phenoxy-isobutyrate.
 6. A therapeutic compositionuseful for treating patients in order to reduce their blood cholesteroland lipids content, which comprises, in association with apharmaceutically acceptable excipient, a therapeutically effectiveamount of at least a compound according to claim 1.